Publications (2)8.24 Total impact
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Article: Intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours: Results from the expansion cohort of a phase I study.
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ABSTRACT: BACKGROUND: Following the dose-escalation stage, this double-blind expansion stage of the phase I study evaluated the safety, pharmacodynamics, pharmacokinetics, anti-vascular effects and antitumour activity of aflibercept 4mg/kg with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: Patients with advanced solid tumours were randomised at cycle-1 to placebo or aflibercept (4mg/kg) on day 1 then irinotecan-LV5FU2 on days 1 and 2. Subsequently, all patients received aflibercept with irinotecan-LV5FU2 every 2weeks. Anti-vascular effects were assessed using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients were treated; 14 received placebo in cycle-1 followed by aflibercept in later cycles and 13 received aflibercept 4mg/kg upfront. The median number of aflibercept cycles was 16 (range 1-44), 12 patients received ⩾20 cycles. Most frequent grade 3/4 adverse events were neutropenia (37%), fatigue (33%) and hypertension (30%). No anti-aflibercept antibodies were detected. Four patients achieved partial responses and 17 had stable disease, lasting >3months in 14 patients. Plasma levels of free over vascular endothelial growth factor-bound aflibercept were adequate, with steady-state achieved from cycle-3. Exploratory DCE-MRI showed no significant perfusion changes with aflibercept. CONCLUSION: Aflibercept 4mg/kg plus irinotecan-LV5FU2 every 2weeks had acceptable toxicity and pharmacokinetics, and showed promising antitumour activity.European journal of cancer (Oxford, England: 1990) 01/2013; · 4.12 Impact Factor -
Article: Phase I dose-escalation study of intravenous aflibercept administered in combination with irinotecan, 5-fluorouracil and leucovorin in patients with advanced solid tumours.
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ABSTRACT: BACKGROUND: To determine dose-limiting toxicities (DLTs), recommended phase II trial dose (RPTD), safety, preliminary antitumour activity and pharmacokinetics of intravenous aflibercept with irinotecan, 5-fluorouracil and leucovorin (LV5FU2). PATIENTS AND METHODS: In this open-label study, 38 patients with advanced solid tumours received aflibercept 2, 4, 5, or 6mg/kg on day 1, then irinotecan and LV5FU2 on days 1 and 2 every 2weeks. RESULTS: Two grade 3/4 aflibercept-associated DLTs occurred with 4mg/kg: proteinuria lasting >2weeks and acute nephrotic syndrome with thrombotic microangiopathy. Two DLTs with 5mg/kg (grade 3 stomatitis and grade 3 oesophagitis reflux) and three with 6mg/kg (febrile neutropenia, grade 3 stomatitis and grade 3 abdominal pain) were considered related to concurrent chemotherapy and underlying disease. The most common grade 3/4 adverse events were neutropenia, hypertension and diarrhoea. Nine patients had partial responses, five with 4mg/kg. Twenty-two patients had stable disease (five with 4mg/kg), lasting >3months in 17 patients. No anti-aflibercept antibodies were detected. Free aflibercept was in excess of bound in most patients on 4mg/kg. CONCLUSION: Based on pharmacokinetics, acceptable safety and encouraging antitumour activity, aflibercept 4mg/kg was selected as the RPTD with irinotecan and LV5FU2 every 2weeks.European journal of cancer (Oxford, England: 1990) 08/2012; · 4.12 Impact Factor
